PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.
PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.
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DOI：
10.1186/s12915-020-00880-7
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发表时间：
2020-10-22
期刊：
影响因子：
5.4
通讯作者：
Farquharson C
中科院分区：
文献类型：
--
作者：
Suchacki KJ;Morton NM;Vary C;Huesa C;Yadav MC;Thomas BJ;Turban S;Bunger L;Ball D;Barrios-Llerena ME;Guntur AR;Khavandgar Z;Cawthorn WP;Ferron M;Karsenty G;Murshed M;Rosen CJ;MacRae VE;Millán JL;Farquharson C
骨骼的经典功能包括运动、保护和矿物质稳态。然而，在小鼠和人类遗传研究中的细胞特异性基因缺失已经确定骨骼是代谢的关键内分泌调节因子。骨特异性磷酸酶，磷酸酶，孤儿1（PHOSPHO 1），这是必不可少的骨矿化，最近已被牵连在人体能量代谢的调节，但其在全身代谢中的作用仍不清楚。在这里，我们通过分析Phospho 1突变小鼠来探索代谢调节的机制。Phospho 1 −/−小鼠表现出改善的基础葡萄糖稳态，并抵抗高脂饮食诱导的体重增加和糖尿病。磷酸化1 −/−小鼠的代谢保护表现在骨钙素水平没有改变。从Phospho 1 −/−小鼠中分离的成骨细胞富含与能量代谢和糖尿病相关的基因; Phospho 1直接和间接地与葡萄糖转运和胰岛素受体信号相关的基因相互作用。在成年Phospho 1 −/−小鼠中观察到的代谢保护作用并不是通过棕色脂肪组织的典型产热作用。然而，Phospho 1 −/−小鼠的血清胆碱水平下降通过喂食2%富含胆碱的饮食而恢复正常，导致胰岛素敏感性和脂肪量恢复正常。我们发现，缺乏骨矿化酶PHOSPHO 1的小鼠表现出改善的基础葡萄糖稳态，并抵抗高脂饮食诱导的体重增加和糖尿病。这项研究确定了PHOSPHO 1作为治疗肥胖和糖尿病的潜在骨源性治疗靶点。
The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear. Here, we probe the mechanism underlying metabolic regulation by analysing Phospho1 mutant mice. Phospho1−/− mice exhibited improved basal glucose homeostasis and resisted high-fat-diet-induced weight gain and diabetes. The metabolic protection in Phospho1−/− mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1−/− mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1−/− mice. However, the decreased serum choline levels in Phospho1−/− mice were normalised by feeding a 2% choline rich diet resulting in a normalisation in insulin sensitivity and fat mass. We show that mice lacking the bone mineralisation enzyme PHOSPHO1 exhibit improved basal glucose homeostasis and resist high-fat-diet-induced weight gain and diabetes. This study identifies PHOSPHO1 as a potential bone-derived therapeutic target for the treatment of obesity and diabetes.
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影响因子：
64.5
作者：
Ferron M;Wei J;Yoshizawa T;Del Fattore A;DePinho RA;Teti A;Ducy P;Karsenty G
通讯作者：
Karsenty G
DOI：
10.1359/jbmr.091023
发表时间：
2010-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Ciancaglini P;Yadav MC;Simão AM;Narisawa S;Pizauro JM;Farquharson C;Hoylaerts MF;Millán JL
通讯作者：
Millán JL
影响因子：
2.4
作者：
Boyde, Alan;Staines, Katherine A.;Farquharson, Colin
通讯作者：
Farquharson, Colin
影响因子：
3
作者：
Bonneau, Jessica;Ferland, Guylaine;Ferron, Mathieu
通讯作者：
Ferron, Mathieu
影响因子：
29
作者：
Cawthorn WP;Scheller EL;Learman BS;Parlee SD;Simon BR;Mori H;Ning X;Bree AJ;Schell B;Broome DT;Soliman SS;DelProposto JL;Lumeng CN;Mitra A;Pandit SV;Gallagher KA;Miller JD;Krishnan V;Hui SK;Bredella MA;Fazeli PK;Klibanski A;Horowitz MC;Rosen CJ;MacDougald OA
通讯作者：
MacDougald OA